A Phase 2b randomized open label trial to assess the quality and balance of dengue immunity elicited by prime-boost combinations of TAK-003 and Butantan-DV

PROJECT SUMMARY Dengue virus (DENV) causes the most common mosquito-borne viral infection in the world, accounting for up to 400 million infections and 20,000 deaths each year. Billions of people live in areas conducive to DENV transmission, and DENV infection is a leading cause of febrile illness in returned travelers. Vaccination represents an essential countermeasure for combating emerging and reemerging infectious diseases like DENV. A major challenge is that DENV comprises genetically and antigenically diverse viruses classified into four serotypes (DENV1-4). Furthermore, as reported in trials for CYD-TDV, vaccination may increase the risk of disease due to DENV infection in some recipients, likely due to antibody-dependent enhancement (ADE). Therefore, generating a humoral immune response that is durable and broadly effective in preventing disease caused by DENV is a critical and unmet goal of DENV vaccine development. To address these gaps, we propose to study DENV immunity induced by heterologous vaccination with the two currently available DENV vaccines within the rigorous framework of a Phase 2b clinical trial. We hypothesize that boosting with Butantan-DV 9 months after a TAK-003 prime will optimally expand DENV serotype-specific and cross-reactive memory B cells, leading to broad durable immunity similar to that following secondary infection with wildtype DENV. This innovative trial will address the significant outstanding question in the DENV vaccine field of whether heterologous prime-boost vaccination is a viable approach to pursue for DENV vaccine programs. As part of per- protocol safety monitoring, we will scrutinize the possibility of vaccine-induced risk of ADE by performing in vitro assays to measure ADE antibodies and conduct unscheduled study visits to thoroughly evaluate any participants experiencing a suspected DENV infection. Immunogenicity in the four study groups will be studied across three specific aims focused on 1) magnitude, specificity, durability, and breadth (across serotypes and within serotype variants) of NAb measured in serologic assays, 2) magnitude, specificity, and kinetics of memory B cell responses and the evolution of the B cell repertoire for two years following vaccination (B cell trajectory), and 3) frequency, specificity, and kinetics of T cell response following vaccination. This study will have immediate and wide-ranging impact, as it addresses a critical need in the DENV field to provide practical and actionable data while delving deeper into immunological mechanisms that may underlie optimally protective adaptive immune responses to DENV elicited by vaccination. In addition to providing data that could justify larger efficacy trial and inform near future public health policy on DENV vaccination, this study will further provide proof-of-concept upon which to build an expanded initiative to examine heterologous vaccination approaches for DENV more broadly, including mixing vaccine platforms, schedules, and antigen composition.